α-Melanocyte-stimulating hormone (α-MSH) is a hormone derived from pro-opiomelanocortin (POMC) (Non-Patent Literature 1), and is referred to as a melanocortin peptide, along with α-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). α-MSH is known to exhibit inhibitory action on the production of inflammation- and fibrosis-associated mediators involved in the occurrence of various pathological conditions, and shows efficacy in autoimmune disease models such as colitis, uveoretinitis, and arthritis (Non-Patent Literature 2). α-MSH analogs have also been developed for use in the treatment of protoporphyria, acute renal failure, or postoperative pain.
Melanocortin receptors (MCRs), which are receptors for α-MSH, are seven-transmembrane G-protein-coupled receptors (GPCRs), and increase intracellular cyclic AMP (cAMP) through their activation (Non-Patent Literature 3). There are five sub-types of MCRs, i.e., from MC1R to MC5R.
MC1R is a receptor that is mainly activated by α-MSH, and is expressed in melanocytes, immune and inflammatory cells, fibroblasts, keratinocytes, endothelial cells, glia cells, and the like. Thus, the activation of MC1R is known to increase the cAMP level in cells in which MC1R are expressed, leading to effects such as homeostasis in the skin against melanogenesis and external stimuli (Non-Patent Literature 4), anti-inflammatory action, and inhibitory action on fibrosis of tissue (Non-Patent Literature 5). MC2R is a receptor that has a low response to α-MSH, and is mainly activated by ACTH. MC2R is mostly expressed in the adrenal cortex. The activation of MC2R is known to have a steroidogenic effect. MC3R is a receptor that is mainly activated by γ-MSH and ACTH, and is expressed in central nerves, macrophages, and the like. The activation of MC3R is known to produce effects such as regulation of autonomic function and anti-inflammatory action. MC4R is a receptor that is mainly activated by α-MSH and ACTH, and is expressed in central nerves and the like. Thus, the activation of MC4R is known to produce effects such as suppression of food intake and erectile function improvement. MC5R is a receptor that is mainly activated by α-MSH, and is expressed in exocrine glands, lymphocytes, and the like. The activation of MC5R is known to produce effects such as regulation of exocrine fluids and regulation of immune function. Therefore, the activation of these melanocortin receptors (MCRs) is expected to provide effects such as immune regulation, anti-inflammation, and suppression of tissue fibrosis, through cAMP formation.
Patent Literatures 1 and 2, for example, are known as documents which disclose pyrrolidine compounds having a carbamoyl group in the 3-position of pyrrolidine. The compounds disclosed in Patent Literature 1, however, are compounds that bind to HDM2 to exhibit anticancer action, which also have an alkyl, aryl, or heteroaryl group as a substituent in the 2-position of pyrrolidine. Thus, Patent Literature 1 does not disclose pyrrolidine compounds having substituents in the 1-, 3-, and 4-positions, like the compounds of the present invention.
The compounds described in Patent Literature 2 are compounds substituted with only a carbamoyl group in the 3-position of pyrrolidine. Thus, Patent Literature 2 does not disclose 3,3-di-substituted pyrrolidine compounds having two substituents in the 3-position of pyrrolidine, like the compounds of the present invention.